We designed 4 different single chain Fv molecules as antigen-recognition domains for anti-CD30 CARs and compared CARs with these different scFvs in vitro. We selected the optimal scFv, and tested it in different CAR designs in vitro and in mouse tumor models. We have identified an optimal scFv and CAR design for further development. This work led to 2 CARs that are both highly effective in mice. We have selected one of these CARs for a phase I clinical trial. Simultaneous work has been completed that has led to generation of a clinical-grade lentiviral vector encoding this CAR. We have completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR, and this protocol has been approved by the NCI Institutional Review Board. We have completed preclinical work to improve anti-CD30 CAR design and T-cell culture methods with an emphasis on comparing different hinge and transmembrane domains as well as comparing CD28 versus 4-1BB costimulatory domains . A clinical trial of T cells expressing an anti-CD30 CAR has opened, and we have treated 20 patients on this trial. Unfortunately, the longest objective duration of response in these patients has been only 3 months. Because of these short durations of response, we have developed genetic constructs that allow one T cell to simultaneously target both CD30 and CD19 with a goal of being able to eliminate both the Hodgkin Reed Sternberg cells and the B cells that are the origin of Reed Sternberg cells.